Rapid Depletion of Intratumoral Regulatory T Cells Induces Synchronized CD8 T- and NK-cell Activation and IFNγ-Dependent Tumor Vessel Regression.

Autor: Kurebayashi Y; Molecular Imaging Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Olkowski CP; Clinical Research Directorate, Frederick National Laboratory for Cancer Research Sponsored by the NCI, Frederick, Maryland., Lane KC; Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, NIH, Rockville, Maryland., Vasalatiy OV; Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, NIH, Rockville, Maryland., Xu BC; Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, NIH, Rockville, Maryland., Okada R; Molecular Imaging Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Furusawa A; Molecular Imaging Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Choyke PL; Molecular Imaging Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Kobayashi H; Molecular Imaging Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland., Sato N; Molecular Imaging Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. saton@mail.nih.gov.
Jazyk: angličtina
Zdroj: Cancer research [Cancer Res] 2021 Jun 01; Vol. 81 (11), pp. 3092-3104. Date of Electronic Publication: 2021 Feb 11.
DOI: 10.1158/0008-5472.CAN-20-2673
Abstrakt: Regulatory T cells (Tregs) are known to inhibit antitumor immunity, yet the specific mechanism by which intratumoral Tregs promote tumor growth remains unclear. To better understand the roles of intratumoral Tregs, we selectively depleted tumor-infiltrating Tregs using anti-CD25-F(ab') 2 near-infrared photoimmunotherapy. Depletion of tumor-infiltrating Tregs induced transient but synchronized IFNγ expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFNγ produced by these CD8 T and NK cells led to efficient and rapid tumor vessel regression, intratumoral ischemia, and tumor necrosis/apoptosis and growth suppression. IFNγ receptor expression on vascular endothelial cells was required for these effects. Similar findings were observed in the early phase of systemic Treg depletion in tumor-bearing Foxp3 DTR mice; combination with IL15 therapy further inhibited tumor growth and achieved increased complete regression. These results indicate the pivotal roles of intratumoral Tregs in maintaining tumor vessels and tumor growth by suppressing CD8 T and NK cells from producing IFNγ, providing insight into the mechanism of Treg-targeting therapies. SIGNIFICANCE: Intratumoral Treg depletion induces synchronized intratumoral CD8 T- and NK-cell activation, IFNγ-dependent tumor vessel regression, and ischemic tumor necrosis/apoptosis, indicating the roles of intratumoral Tregs to support the tumor vasculature. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/11/3092/F1.large.jpg.
(©2021 American Association for Cancer Research.)
Databáze: MEDLINE
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